Breast MRI

5/24/2018 Breast MRI

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Review

Invited

Dynamic Image Interpretation of MRI of the Breast

Christiane K. Kuhl, MD* and Hans H. Schild, MD

Dynamic breast MRI provides information on both lesioncross-sectional morphology and functional lesion featuressuch as vascularity/perfusion and vessel permeability. Thisreview gives an overview of the historical background of dy-namic contrast-enhanced breast MRI. It explains the tech-niques pathophysiological basis, describes the varioustechnical approaches that have been pursued and the corre-sponding interpretation guidelines that have been proposed(including their respective diagnostic accuracies), and pre-sents established and evolving clinical applications of the

dynamic approach to breast MRI. J. Magn. Reson. Imag-ing 2000;12:965974. 2000 Wiley-Liss, Inc.

Index terms: breast cancer; MR imaging; differential diagno-sis; contrast enhancement kinetics; BRCA; angiogenesis

UNDOUBTEDLY, MRI IS THE MOST SENSITIVE TECH-NIQUE that is currently available for imaging primary orrecurrent breast cancer. It has been shown to be extraor-dinarily useful for predicting disease extent, differentiat-ing scar from recurrent cancer, identifying primary can-cer in young high-risk patients, and evaluating tumorresponse to neoadjuvant chemotherapy (15).

Despite its obvious and well-established utility, the

technique still awaits its introduction into routine clin-ical breast imaging. There are several reasons for this,

but probably the most important one is the lack ofstandardizationboth in terms of technique as well asin terms of interpretation guidelines. If one searches thepublished literature for breast MRI, one will be over-

whelmed by a myriad of technical approaches and aseemingly unlimited number of diagnostic criteria. Ev-ery group seems to use different techniques, with dif-ferent criteria; none of them are concordant, everybodychooses something else for threshold, nothing issurein short: it is a diagnostic chaos. The conse-quence is that potential users of breast MRI are left withthe impression that this technique is unlikely to be-come clinically useful in the foreseeable future, becausenothing can be regarded as established knowledge.

The purpose of this review is to explain how the var-ious techniques of dynamic breast MRI evolved, whatthe underlying assumptions are, where the difficultiesare, how it should be used in a clinical setting, and

most importantlyto explain what the overall tendencyin the field is.

HISTORICAL OVERVIEW

After the introduction of gadolinium dimeglumine asMR contrast agent, several different approaches have

been developed for MRI of the breast. Heywang et al (6)were the first to use gadolinium dimeglumine for MRI of

the breast. They reported strong contrast enhancementof breast cancers, whereas the normal parenchyma ex-hibited only weak (if any) enhancement. Heywang sug-gested a technique that today would be called a semi-dynamic acquisition: they acquired one pre-contrastand two post-contrast image stacks. The main reasonfor obtaining the second post-contrast stack was toensure detection of lesions with delayed enhancementthat may be missed on the first post-contrast image.Imaging was performed with limited temporal and rel-atively high spatial resolution. Since temporal resolu-tion was not the main focus, a 3D gradient echo tech-nique could be applied.

The approach launched by Kaiser et al (7) was de-signed to track the rapid signal intensity changes thatoccur in the early post-contrast period. The techniquethey proposed could be called the archetype of dynamic

breast MRI: they suggested acquiring one pre-contrastand a series of post-contrast image stacks including

both breasts at the highest possible temporal resolution(60 sec). Rapid imaging at that time allowed only alimited spatial resolution and acquisition of only asmall number of sections (510), such that only half ofthe parenchymal volume was covered. Because rapidimaging was necessary, image subtraction was used tosuppress the signal from fatty tissues, rather than ap-plying time-consuming active fat suppression tech-

niques.The concept of Harms et al (8) was based on the

well-established fact that malignant lesions exhibitcharacteristic morphologic features that distinguishthem from benign lesions. To improve analysis of subtlemorphologic details, they advocated a technique thatmay serve as the archetype of static breast imaging:imaging of one single breast with high spatial resolution

before and after contrast material injection. Since tem-poral resolution was not an issue in this approach, 3Dgradient echo imaging was used, and fat suppressionensued by means of spectral pre-pulses (which wererather time consuming).

Department of Radiology, University of Bonn, Bonn, Germany.

*Address reprint requests to: C.K., Department of Radiology, Universityof Bonn, Sigmund-Freud-Str. 25, D-53105 Bonn, Germany. E-mail:[email protected]

Received August 16, 2000; Accepted September 15, 2000.

JOURNAL OF MAGNETIC RESONANCE IMAGING 12:965974 (2000)

2000 Wiley-Liss, Inc. 965


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The two fundamental schools that evolved (and thatwere also separated geographically) were the dynamicschool and the static school. The dynamic school(most popular in European countries) attempted to dis-tinguish benign and malignant lesions by enhancementcharacteristics at high temporal resolution imaging.

The static school (most popular in the U.S.) attempted

the same by evaluating morphologic features of en-hancing lesions at high spatial resolution. Due to thesevere technical constraints, particularly during theearly days of breast MRI, it was necessary to choose

between either temporal or spatial resolution, depend-ing on the diagnostic criterion that was given priority.

Accordingly, the fundamentally different approachespublished in the literature are merely a reflection of thefact that breast MRI is technically extremely challeng-ing. The diverging demands of an optimal temporal andspatial resolution for the detection and classification ofenhancing lesions can hardly be met even with todaysequipment. Because researchers had to cope with thetechnical shortcomings of their equipment, they started

doing breast MRI at the two ends of the spectrum ofimaging techniques that are suitable for breast MRI.

It is important not to misunderstand these differentapproaches as being contradictory or as being compet-itors for the ultimate truth. They are not meant to beused as alternatives, but have to be understood withinthe clinical and technical context of the time when they

were written and published. Today, owing to the tech-nical progress that has been made, it is possible tointegrate these demands rather than compromising onone or the other. Therefore, modern concepts of breastMRI strive to consider both lesion morphology and con-trast enhancement kinetics (9,10). As a consequence,

today there is considerable agreement in terms of whatconstitutes an appropriate pulse sequence for breastMRI. It is widely accepted that temporal resolution is anecessitynot only if one wishes to evaluate contrastenhancement kinetics, but also to improve the analysisof morphological details (10 12). This is due to the factthat lesion-to-parenchyma contrast is best only in theearly post-contrast period, whereas it deteriorates pro-gressively in the intermediate and late post-contrastphase.

PATHOPHYSIOLOGICAL BASIS

The pathophysiological basis of lesion contrast en-hancement in breast MRI has not yet been fully eluci-dated, but some fundamental facts are known thatshould help understand the techniques specificstrengths and weaknesses in terms of lesion detectionand differential diagnosis.

It is a well established fact that malignant lesionsrelease angiogenic factors (e.g., vascular endothelialgrowth factor (VEGF)) that induce sprouting andgrowth of pre-existing capillaries, and induce the denovo formation of new vessels (1315). As revealed byhistologic and electron microscopic studies, these cap-illaries exhibit a pathologic vessel wall architecture withleaky endothelial linings. Thus, the effect of angiogenic

activity is twofold: there is an increased vascularity(vessel density), leading to a focally increased inflow of

contrast material, plus an increased vessel permeabil-ity, leading to an accelerated extravasation of contrastmaterial at the site of the tumor. Because the regularcapillary architecture is only poorly reconstructed, ar-terio-venous shunts are another hallmark of tumor-induced angiogenesis, leading to perfusion shortcuts.

To date, however, it is unclear what exactly deter-

mines the degree of contrast material enhancementseen on the MR image. Many studies have been pub-lished, correlating vessel density with signal intensitychanges (1625). The results are contradictory, but

what can be stated thus far is that vessel density itselfcannot be the only contributor. A possible reason forthe inconsistent correlation between MR-detected en-hancement and vessel density or prognostic factors isthe fact that the gadolinium-induced signal intensityincrease in T1-weighted MR images is not exactly pro-portional to the amount (or concentration) of contrastmaterial that accumulates in a lesion. Lesion enhance-ment is determined by a variety of contributing factors,including vessel permeability, but also contrast mate-

rial diffusion rates, composition of the interstitial tumormatrix, and baseline and post-contrast tissue T1 relax-ation times. Because signal intensity in susceptibility-

based T2*-weighted first-pass perfusion imaging ismore directly related to vessel density and angiogene-sis-induced pathologic vessel permeability, it has beensuggested to use this technique as an adjunct to reg-ular T1-weighted dynamic imaging to improve differ-ential diagnosis of enhancing lesions (26).

What is even more problematic from the clinical ra-diologists perspective is the fact that a locally increased

vascularity and/or capillary permeability is by nomeans specific for malignant tissues. Almost all benign

neoplastic lesions, and many benign non-neoplasticstates, go along with a significant hypervascularity orhyperemia. Accordingly, contrast enhancement per se,or even strong and rapid contrast enhancement, is nota feature that is reserved for malignant lesions. How-ever, a low vascular density can be also found in somemalignant changes. Although a non-enhancing inva-sive breast cancer is so rare that this finding merits acase report (27), tumors with only shallow enhance-ment do occur in up to 10% of cases, notably in truelobular-invasive cancers and in the scirrhotic or des-moplastic type of ductal invasive breast cancer. Basedon histochemical studies it is now assumed that theentire process of angiogenesis differs in these types of

breast cancers. There is evidence that in lobular-inva-sive cancers angiogenesis is mediated by angiogenicfactors other than VEGF (28). Some well-differentiatedinvasive cancers (e.g., the tubular type) may go withouta significant degree of angiogenesis as well. Moreover,an interaction between tumor cells with the adjacentstroma is not necessarily found in in situ cancers(29,30). So while a certain degree of angiogenic activityseems to be a prerequisite for tissue invasion, and isthus closely associated with malignant growth, this isnot necessarily to be expected for DCIS. Accordingly,contrast enhancement of DCIS can be predicted to varyeven more than that of invasive cancers and will be

below any reasonable enhancement thresholds in aconsiderable number of cases.

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These pathophysiologic facts explain why vascular-ity, and hence contrast enhancement patterns, varysuch that a clear-cut differential diagnosis based oncontrast enhancement should prove impossible. It isquite evident that contrast enhancement itself cannot

be more specific or more sensitive than the biological (orpathophysiologic) basis it stands for: hypervascularity

(or lack thereof) is not pathognomonic for malignant orbenign lesions. Yet, suprisingly enough, the differentialdiagnostic power of evaluating lesion contrast enhance-ment is somewhat better than one might expect giventhe nonspecific distribution of vessel densities among

benign and malignant lesions. The explanation for thisphenomenon is probably the fact that it is not the merenumber of vessels, but rather the entirety of vesselarchitecture, permeability, and tissue relaxation timesthat determines contrast enhancement, and, thus, dif-ferential diagnosis in dynamic breast MRI.

DIAGNOSTIC CRITERIA AND THEIR ACCURACY

Based on the imaging technique proposed by Kaiser etal (7) and Heywang et al (31), many more dynamicacquisition schemes have been developed, and almostas many interpretation guidelines. For analysis of le-sion enhancement, Heywang et al (31) suggested quan-tifying a normalized enhancement ratio by assessingthe lesions signal intensity relative to the signal of fattytissue. After analyzing normalized lesion signal inten-sities (NU) in a cohort of 144 patients with benign andmalignant breast diseases, they proposed a classifica-tion scheme that was based on lesion peak signal in-tensity increase. Lesions with a maximum signal inten-sity increase at or beyond the threshold of 300 NU were

classified as malignant. Between 250300 NU theywere rated borderline, and an enhancement below 250NU was considered nonsignificant. Accordingly, theirapproach to differential diagnosis would be based onthe question: How strongly does the lesion enhance?Using this criterion, they reported a sensitivity of 100%(71/71), and specificity of 27% (20/73).

Kaiser et al (7) suggested a quantification of lesionenhancement as well. However, they proposed normal-izing enhancement not with respect to the signal fromfatty tissue, but with respect to baseline lesion signalintensity, according to the equation:

[(SIpost SI pre)/SIpre] 100,

where SIpre is the signal intensity before contrast, SIpostis the signal intensity after contrast administration. Ina preliminary study of 25 patients, they found that

breast cancers exhibit faster enhancement rates, caus-ing a strong signal increase in the early post-contrastperiod. For differential diagnosis, enhancement velocity(relative SI increase per minute in the early post-con-trast period) was suggested. Kaiser found that malig-nant lesions revealed an enhancement velocity beyonda threshold of 100% (i.e., doubling signal intensity

within the first post-contrast minute). Accordingly, they

suggested establishing the differential diagnosis basedon the question: How fast does the lesion enhance?

Using this approach in a preliminary series of 25patients, Kaiser reported a sensitivity of 100% (6/6).Unfortunately, however, the authors failed to validatetheir data in a larger series of patients. In several sub-sequent review articles that were published in the firsthalf of the last decade, Kaiser and coworkers stated thatthe sensitivity and specificity of their approach was

99% and 98%, respectively (32,33). Notwithstandingthe rather poor validation, this imaging technique andits associated criteria have gained considerable popu-larity. Stomper et al (34), using the same technique ona small series of patients, reported a sensitivity of 92%(23/25), but achieved only a moderate specificity (61%,16/26).

As did Kaiser, Gilles et al (35) suggested a dynamictechnique focussing on temporal resolution. Theyfound that differential diagnosis could be based on de-termining the time point of lesion enhancement relativeto arterial enhancement, and they suggested that everylesion that exhibits enhancement on the first post-con-trast image (i.e., 94 sec post-injections) was to be con-

sidered malignant. Accordingly, their approach to dif-ferential diagnosis would be based on the question:

When does the lesion start to enhance?

Gilles and coworkers tested their approach in a seriesof 134 patients with 64 malignant and 79 benign le-sions. They achieved a sensitivity of 95% (61/64) and aspecificity of 53% (42/79).

The concept of analyzing onset of lesion enhancementwas also pursued by Boetes et al (36). They used anultrafast imaging technique that sacrificed coverage ofthe entire breast parenchyma in favor of a single-sec-tion, ultra-fast bilateral image acquisition based onturbo gradient echo sequences with a temporal resolu-

tion of 2.3 sec. Boetes and colleagues observed thatmalignant lesions start to enhance 11.5 sec after bolusarrival in the descending aorta. Moreover, they reportedthat the spatial distribution of contrast material en-hancement within a lesion differs for breast cancersand benign lesions. They observed that in malignantlesions enhancement starts in the periphery andprogresses from there in a centripetal fashion. Benigntumors, on the other hand, show a centrifugal enhance-ment pattern. Accordingly, their approach to differen-tial diagnosis would be based on the question: Whendoes the lesion start to enhance, and where within the

lesion does it start?

Using these criteria in a cohort of 87 lesions, Boeteset al (36) achieved a sensitivity and specificity of 95%(62/65) and 86% (19/22), respectively. Schorn et al (37)tried the same technique and the same diagnostic cri-teria on a series of 35 lesions (15 malignant and 20

benign). In their small series, they could not reproducea statistically significant difference concerning the pro-gression of enhancement (centripetal or centrifugal) orthe onset of lesion enhancement for benign and malig-nant lesions. The reason for this discrepancy remainsspeculative; but differences concerning the distributionof benign and malignant lesions in the respective studygroups or concerning the average lesion size may ac-count for it.

Fischer et al (38) as well as our group (10) suggestedthat in addition to the early post-contrast period, the

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Figure 1.

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intermediate and late post-contrast phases also yielddiagnostically useful information. Analysis of lesioncontrast enhancement behavior in these phases can beused as an additional criterion with analyses of otherdynamic imaging features. We suggested a qualitativeevaluation of lesion signal intensity time courses basedon a visual classification of the shape of the time/signal

intensity curve. The classification scheme distin-guishes types 1a and 1b, type 2, and type 3 timecourses. Enhancement is classified as type 1a if thelesion continues to enhance over the entire acquisitionperiod. It is classified as type 1b if in the late post-contrast phase the signal gain is slowed down, yieldinga bowing of the signal curve. Enhancement is classifiedas type 2 if the signal plateaus after the early increase.

A type 3 curve is assigned in cases where there is a lossof signal intensity due to wash-out of contrast materialoccurring immediately after the signal intensity peak.Lesions with steady signal intensity increase (types 1aand 1b) were more likely to be benign, whereas lesions

with signal intensity plateau (type 2) or with a wash-out

of contrast material (type 3) tend to be malignant. Ac-cordingly, this approach to differential diagnosis would

be based on the question:What happens after the ini-tial signal increase?

Using this criterion, in a cohort of 266 contrast-en-hancing lesions (10) qualitative evaluation of signal in-tensity time courses yielded a sensitivity of 91% (92/101) and a specificity of 83% (137/164).

All these approaches were triggered by the fact thatwhile breast cancers exhibit contrast enhancement,many benign lesions do so as well. Consequently, fordifferential diagnosis it is necessary to assess addi-tional lesion features. The many different ways to as-

sess contrast enhancement kinetics, and the variousterms describing kinetic parameters that have beenlisted, should not be misunderstood as discrepancies orscientific inconsistency. Rather, they represent differ-ent ways to look at the same phenomenon: the early,

rapid, and strong signal intensity increase that occursin breast cancers. Likewise, the many different thresh-olds that have been proposed to establish cut-off val-ues for suspicious enhancement should not be mis-understood as giving proof of an inherent inconsistencyin the dynamic approach. The exact numbers of thresh-old values will vary greatly with the field strength, pulse

sequence, and timing of contrast material injection. Assuch, they are not stand-alone data, and they are notvalid except for the particular setting in which theyhave been established.

TECHNICAL ISSUES

The use of a dedicated surface coil is a prerequisite forbreast MRI, be it static or dynamic. Usually, for dy-namic imaging a double-breast coil is used to allowimaging of both breasts simultaneously. Owing to thediverging demands of an adequate temporal and anoptimum spatial resolution, breast MRI is technicallydemanding and clearly profits from high magnetic

fields. It has been shown, however, that breast MRI itcan be successfully performed at mid-field systems(0.5T) (39,40).

The basis of dynamic breast MRI is the T1-weightedgradient echo pulse sequence. Due to their superior

T1-contrast and shorter acquisition times, gradientecho sequences are generally preferred over spin echopulse sequences. For dynamic imaging, both 2D and 3Dacquisition schemes are suitable. The exact design ofthe dynamic series will vary depending on the diagnos-tic criterion that is primarily used: If onset of enhance-ment is to be evaluated, then ultrafast imaging is nec-essary. With current state-of-the-art equipment this

will only be possible with a single-section technique.Therefore, this approach will only be suitable for lesioncharacterization (not for lesion detection) because thelocation of the lesion must be known in advance toposition the slice. Accordingly, this technique has not

Figure 1. Preoperative breast MRI for staging of suspected breast cancer. A 57-year-old patient received a screening mammo-gram. A solitary spiculated mass in the lower-outer quadrant of her right breast was rated as BIRADS 5. Breast MRI wasperformed preoperatively because breast conservation was considered. Dynamic breast MRI was performed using our standardT1-weighted 2D gradient echo series (TR/TE/FA 260/4.6/90). One image stack (with 33 sections) was acquired before contrast,and five were obtained after bolus injection of 0.1 mmol/kg BW gadolinium dimeglumine. Acquisition time of each image stack

(temporal resolution) 1 min 45 sec; imaging matrix 390 512, section thickness 3 mm. Image subtraction was used tosuppress the signal from fatty tissue. Signal intensity time courses were calculated. a: pre-contrast image of the known lesionin the lower outer quadrant; b: first post-contrast image of the dynamic series of the same location; c: subtracted image;d:pre-contrast image of a section through the cephalad parts of the upper quadrant;e: first post-contrast image of the dynamicseries of the same location; f: subtracted image (ef); g: signal intensity time course of the lesions in the upper quadrant;h: maximum intensity projection image of all sections of the first post-contrast dynamic image stack (subtracted). Note thestellate lesion in the lower outer quadrant, with rapid and strong signal intensity increase in ac. The lesion corresponds to themammographically visible index lesion. Note the irregular configuration and the heterogeneous internal architecture that isclearly visualized. In addition to the mammographically visible lesion in a, two other enhancing lesions were identified in theupper inner and upper outer quadrant (dg). Note the rapid enhancement, the irregular morphology, and the suspicious contrastenhancement pattern with wash-out of the signal intensity time course (curve type 3). The lesions were rated as highlysuspicious for invasive breast cancer. The MIP image (h) provides a good overview on the location of the lesions in the lower outer,upper outer, and upper inner quadrant. Breast MR confirms the absence of breast cancer in the left breast. The patient wasoperated on after MR-guided localization of the clinically and conventionally occult lesions in the upper part of the breast.Histology revealed a multicentric but highly differentiated invasive tubular carcinoma (one in the lower quadrant, 6 mm in size;

and two in the upper quadrants, 4 mm each), yielding a stage pT1b mN0M0. Owing to the small size of the lesions relative to thesize of the breast, and due to the good prognosis of tubular cancer, breast conservation surgery was performed.



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gained widespread use. The vast majority of dynamicimaging techniques that are used for clinical breastimaging today are designed to allow evaluation of ki-netic and morphologic parameters (4,1012,41). There-fore, an in-plane pixel size of about 1 mm is recom-mended, with a section thickness of no more than 3mm. To be able to track the rapid signal intensity

changes that occur in the early post-contrast period,and to ensure high lesion-to-parenchyma contrast, aminimum temporal resolution is required. What exactlyconstitutes minimum temporal resolution is, how-ever, still a matter of debate. It is generally felt that theacquisition time of one dynamic image stack shouldtake less than two minutes; ideally, it should be aroundone minute. (These values are derived from clinicalpractice; as yet, these recommendations have not beensubstantiated by prospective trials.) Because bilateralimaging is performed over a relatively large field of view(FOV), and because a rapid image acquisition is neces-sary, active fat suppression techniques are not an op-tion. Instead, image subtraction is used to suppress the

signal from fatty tissue.The dynamic imaging protocol used at our institution

may serve as an example (Fig. 1). It is a 2D gradientecho series with TR/TE/FA 260/4.6/90; 390 512imaging matrix; FOV of 290 310 mm; section thicknessof 3 mm, with 33 sections; and temporal resolution of1:45 sec per dynamic stack. One set of images is ac-quired before contrast, and another five image stacksafter bolus i.v. injection (4 mL/sec) of 0.1 mmol/kggadolinium dimeglumine, followed by a saline flush. Toquantify enhancement, signal intensity is measured viaROIs that are selectively placed into the area of a lesionin which the earliest enhancement occurs. Enhance-

ment velocity is quantified via the enhancement for-mula mentioned above; the time course of signal inten-sity is assessed visually.

HOW TO USE INFORMATION OBTAINED FROMDYNAMIC DATA

Owing to the biologic and histologic heterogeneity ofbreast lesions mentioned above, it should go withoutsaying that it is not possible to diagnose breast cancers

with a simple enhancement cut-off value or threshold.An enhancement threshold may enable the character-ization of a substantial number of enhancing le-sionsas long as they exhibit a typical contrast en-hancement. Yet, because far from all lesions enhanceas expected, this concept will cause an unacceptablyhigh rate of false-positive or (even more fatal) false-negative decisions on lesions that behave less typically.

To avoid any false-negative decisions, a threshold mustbe set at relatively moderate enhancement values; how-ever, a myriad of benign lesions will then reach supra-threshold enhancement. There is extensive evidence inthe literature suggesting that many benign lesions (fi-

broadenomas, focal adenosis, proliferative dyplasia,papillomas, focal chronic mastitis, fresh fat necrosis,hyperplastic intramammary lymph nodes, and evennormal breast parenchyma under hormonal stimula-

tion) may go along with contrast enhancement ratesthat may be well beyond any reasonable cut-off value

(26,4244). On the other hand, even with low cut-offvalues, there will be breast cancers that fail to meet therequired enhancementmostly lobular, scirrhoticductal, mucinous, and tubular invasive cancers arecandidates for such below-threshold enhancement(45). As a consequence, dynamic data (enhancement

velocity, degree, onset, and so forth) must not be used

as stand-alone diagnostic criterion. Instead, theyshould be integrated in the process of differential diag-nosticto expand(rather than narrow) the armamen-tarium of differential diagnosis in breast MRI.

We use the following guidelines (10): For interpreta-tion of dynamic breast MR images, we first refer to thefirst post-contrast image stack and search for lesions

with significant enhancement, because lesions that ap-pear at this phase are associated with a significantprobability of malignancy. Once such a lesion is iden-tified, morphology is evaluated. If morphology is suspi-cious, biopsy is recommended. If morphology is equiv-ocal or benign, the time course of signal intensity isevaluated. If a type 3 time course is identified, biopsy is

recommended. If it is a type 1 or 2 time course, weusually recommend follow-up.

If a lesion with shallow enhancement is identified, themanagement decisions are based solely on lesion mor-phology, in order to include, e.g., lobular cancer orDCIS (46). The lesions internal architecture (47) is con-sidered such that if rim enhancement is identified bi-opsy is recommended irrespective of other findings. Ifinternal septations are clearly discernible, diagnosis offibroadenoma is establishedagain irrespective ofother findings, including kinetic data. In addition, asadjunctive criteria we consider the progression of en-hancement (centripetal/centrifugal), and the lesions

signal intensity in T2-weighted images (48).It should be well understood that these guidelines are

not carved in stone, but must be adapted to the indi-vidual patients situation by considering the clinicalfindings, the findings in conventional imaging modali-ties, the patients age, her medical history includingmenstrual status or hormone medication, and familyhistory.

CURRENT APPLICATIONS OF DYNAMICBREAST MRI

There are several indications for breast MRI; however,

at this stage, there are virtually no data available thatwould allow end-point analyses to be performed on theinfluence of breast MRI in terms of survival, mortality,morbidity, or quality of life issues.

Clarification of Inconclusive Conventional

Imaging Findings

Breast MRI offers a wealth of information on the lesionin question. It provides detailed information on high-resolution, high-contrast cross-sectional tumor mor-phology, and insight into tumor biology, angiogeneticactivity, T1- and T2-relaxation rates, contrast agentrelaxivity, etc.all the physical and biochemical fea-

tures that determine image contrast on MR studies. Themany parameters that contribute to lesion appearance

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translate into a full battery of differential diagnosticcriteria. These may be used to distinguish benign andmalignant lesions even in cases that are inconclusiveon conventional imaging. Specifically, dynamic breastMRI may be useful in evaluating lesions that appearmorphologically benign on conventional imaging stud-ies. The evaluation of time course kinetics introduces a

completely independent diagnostic parameter (i.e., tis-sue perfusion/diffusion/vessel permeability) that canhelp distinguish benign lesions (e.g., fibroadenoma)from well-circumscribed breast cancer. If, for example,a breast cancer looks benign in terms of morphology, acorrect diagnosis may still be possible if signal intensitytime courses are evaluated (4,10,11).

It should be noted, however, that if breast MRI is to beused for clarification of mammographically or sono-graphically suspicious lesions, then it is an importantprerequisite that the radiologist be familiar with thespecific limitations of all three imaging modalities. It isimportant to realize that there are specific constella-tions of mammographic or sonographic findings that

may not be clarified by a negative breast MRI, whereasin others MRI can be used to obviate the need for bi-opsy. The former holds true for example, for cases withsuspicious mammographic microcalcifications. Be-cause sensitivity of breast MRI for in-situ cancers islimited, it may not be used to exclude underlying DCIS(30). The latter holds true for example, if tumor recur-rence has to be ruled out in a stellate density after

breast conservation therapy (49). Moreover, it shouldbe remembered that, in general, percutaneous core bi-opsy may be more appropriate to definitively clarifyconventionally inconclusive lesions.

Staging

If on conventional imaging studies a solitary focus ofbreast cancer has been identified and a breast conserv-ing therapy is considered, preoperative breast MRI isindicated to rule out or localize additional breast cancerfoci. In a recent article, Fischer et al (41) reported onpreoperative dynamic breast MRI for local staging ofpatients who were candidates for breast conservation.

They diagnosed therapeutically relevant additionalfindings in 16% of cases. Becausedynamicbreast MRI(as opposed to high-spatial-resolution static breastMRI) allows the simultaneous evaluation of both

breasts, a screening of the contralateral breast willalways be performed. This is reasonable because a syn-chronous contralateral breast cancer will be present inas many as 6% of patients (41).

Assessing Tumor Response to Neoadjuvant

Chemotherapy

Neoadjuvant chemotherapy is increasingly used in pa-tients with locally advanced breast cancer (LABC) forrestoring operability as well as for systemic treatment ofpossible concomitant lymph node or distant metasta-ses. Conventional imaging techniques, however, offeronly a poor diagnostic accuracy for the assessment of

chemotherapeutic effects (50). This is mainly due to thefact that after effective chemotherapy tumor tissue may

be replaced by diffuse fibrosis. The fibrous tissue maysimulate residual tumor upon clinical palpation, and itmay interfere with an accurate depiction of residualtumor on both mammograms and breast ultrasound(US) studies. Moreover, for optimizing patient care as

well as for economic reasons, it is crucial to reliablyidentify non-responders as soon as possible. There is

evidence that dynamic breast MRI is ideally suited tofulfill both of these tasks.

Evaluation of Chemotherapy Response

In addition to tumor morphology, dynamic breast MRIis able to quantify functional tissue parameters, suchas tumor perfusion, as a surrogate marker for tissue

viability. Because dynamic breast MRI is able to detectand quantify chemotherapy-induced changes of malig-nant tissues perfusion or viability, this can be exploitedfor assessing tumor response to neoadjuvant chemo-therapy. Several groups have investigated whether dy-namic breast MRI can identify responders or non-re-

sponders (5,5154). With a remarkable consistency, thedifferent studies revealed that after just one or twochemotherapy cycles, and before a measurable changeof tumor size occurred, response to chemotherapy washeralded by a substantial change of contrast enhance-ment patterns. Decreasing enhancement rates, a flat-tening of the signal intensity time course, and a re-duced degree of enhancement are the hallmarks ofearly tumor response to chemotherapy. Although thesample size of the studies is small, there is sufficientevidence to conclude that patients with a completelyunchanged contrast enhancement pattern after twochemotherapy cycles can be classified as non-respond-ers. Given the high clinical and economical relevance ofan early identification of non-responders, this mayemerge as one of the most important applications fordynamic breast MRI.

Evaluation of Residual Tumor

Several studies have confirmed thatcompared to con-ventional imaging modalitiesbreast MRI is muchmore sensitive and specific for assessing residual tu-mor extent after chemotherapy (51,5557). It should be

well understood, however, that although breast MRImay be better than clinical assessment or conventionalimaging, it is still far from being perfect. Scattered re-

sidual vital cancer cells in the former tumor bed inresponders may not enhance after contrast, thus es-caping the diagnosis. It is a well established fact thatthese tumor remnants do not influence prognosis and,thus, the classification of response; however, if induc-tion chemotherapy is performed with the ultimate goalof breast conservation, breast MRI cannot be used torule out residual micro-manifestations in responders,and it may not be able to identify patients who areamenable to breast conservation after induction che-motherapy.

High-Risk Screening

Women with proved BRCA mutation or with a familyhistory suggestive of hereditary breast cancer face an



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8090% lifetime risk of being diagnosed with breast

cancer. Moreover, these women tend to develop breast

cancer at significantly younger ages (i.e., in their early

thirties) than the genetically intact woman. Accord-

ingly, these women require an intensified screening

starting at age 2530. In these very young women, how-

ever, the sensitivity of mammography may be signifi-

cantly reduced. Recently, we published our experienceswith dynamic breast MRI screening in high-risk women

diagnosed or suspected to carry a breast cancer sus-

ceptibility gene (4). Our results document that dynamic

breast MRI is clearly superior to both mammography

and breast US for early detection and classification of

breast cancers. The dynamic approach seems to be

particularly useful here for three reasons:

First, in a screening setting, bilateral imaging is re-

quired. Dynamic imaging is almost always done with

coverage of both breasts, whereas high-spatial-resolu-

tion static MRI can only be performed on one breast at

a time.

Second, our results show that BRCA1-induced breastcancers in particular exhibit atypical morphologic fea-

tures. Even on gross pathology or low-magnification

histology, these tumors may appear completely well-

circumscribed, with no evidence of infiltration. Accord-

ingly, even with the highest spatial resolution imaging,

these tumors may not be distinguishable from the

many fibroadenomas that plague mammographic inter-

pretation of patients of this age group. Dynamic breast

MRI, however, allows additional evaluation of tissue

perfusion or angiogenetic activity. We have shown that

tumors with deceptively benign morphology exhibit

highly suspicious contrast enhancement kinetics with

early, rapid, and strong signal intensity increase, fol-

lowed by a wash-out of signal intensity (time course

type 3). Thus, in spite of the apparently benign morpho-

logic features of hereditary breast cancers, a true-pos-

itive diagnosis was possible in all cases based on dy-

namic MRI. Accordingly, sensitivity of breast MRI vs.

mammography and breast US combined was 100% vs.

44%.

Third, in very young women, hormonal stimulation

may produce pseudo-lesions, i.e., focal contrast-en-

hancing areas that are not associated with any struc-

tural changes of the parenchymal composition but are

probably caused by the local histamine-like effects of

ovarian steroid hormones. These pseudo-lesions are ex-

tremely prevalent in younger patients; they are a noto-rious cause of false-positive findings in breast MRI

studies. It has been shown that these lesions can ex-

hibit an alarmingly irregular morphology. However,

contrast enhancement kinetics (particularly the signal

intensity time courses) correspond to the benign type

1 time course in the vast majority of cases. Thus time

course analysis can help correctly classify these pseu-

do-lesions as benign. Accordingly, in our series of al-

most 200 women receiving 350 MRI studies, breast MRI

had the lowest false-positive rate of all imaging modal-

ities under investigation (mammography, US, and MRI).

Therefore, the positive predictive value of breast MRI

(64%) was significantly higher than that of mammogra-phy (44%) or breast US (12%).

It can be concluded that dynamic breast MRI enablesadequate surveillance and early diagnosis of the high-risk patient with hereditary breast cancer. Accordingly,

breast MRI screening may someday be used as an al-ternative to prophylactic bilateral mastectomy, which iscurrently the standard treatment option for the many

young women who are suspected gene carriers. Further

studies (particularly multicenter outcome studies) willhave to elucidate whether MRI screening can effectivelyreplace bilateral prophylactic mastectomy for prevent-ing BRCA-induced breast cancer mortality.

Assessing Tumor Grade and Prognosis

It has been extensively shown that tumor vascularity,as revealed by histologic vessel density counts, corre-lates with tumor aggressiveness and malignant (partic-ularly metastatic) potential (29,58 61,63). Becausecontrast enhancement patterns in dynamic breast MRIseem to be linked with hypervascularity (1618,2022),the intriguing thought came up that dynamic breast

MRI might be useful for tumor grading, or assessingtumor aggressiveness or prognosis in vivo. Several re-ports have been published investigating the correlation

between contrast enhancement rates or time coursefeatures and prognostic factors such as histologicalgrading, lymph node status, S-phase fraction, andmodern proliferation indices (oncogenes/tumor sup-pressor genes) such as c-erbB-1, c-erB-2, p53, or Ki-67.Unfortunately, however, the results of these studies

were inconsistent. In two prospective studies, no corre-lation with any of the criteria used in dynamic breastMRI (enhancement rates, maximum enhancement,

wash-out rates, etc.) has been obtained (62,64). Yetthere are two studies that revealed a highly significant

correlation between contrast enhancement in dynamicMRI and prognostic factors: Mussurakis (65) reportedon a strong correlation of enhancement rates and tu-mor grading as well as nodal status in 53 patients withinvasive breast cancers; Bone et al (66) confirmed thesefindings in another 50 breast cancer cases.

To date the source of the discrepancy between thepublished studies is unclear. It is possible that the

variability in determining contrast enhancement ratesif manually drawn ROIs are used may account for someheterogeneity of results. This is supported by the reportof Mussurakis et al (67) that a statistically significantcorrelation between enhancement rates and prognostic

factors was only obtained if an automatic ROI definitionbased on parametric images was used (51).

Studies on contrast-enhanced dynamic breast MRI ofR3230 implanted adenocarcinoma have been per-formed using new blood-pool contrast agents, allowingthe assessment of tumor vessel permeability, and thusof tumor angiogenic activity grading (6871). Hopes arehigh that once these agents are available for use inhumans, a noninvasive in vivo grading of breast can-cers based on preoperative breast MRI will become fea-sible.

FUTURE DIRECTION

In the field of breast MRI, extensive discussions overdiscrepant technologies and interpretation guidelines

972 Kuhl and Schild


9/10

have for a long time prevented the acceptance of thetechnique, and precluded the organization and perfor-mance of multi-institutional trials that are urgentlyneeded to document the long-term utility of the tech-nique in breast cancer patients. The most importantargument against the introduction of breast MRI intoroutine clinical practice is that it is a nonstandardized

and nonstandardizable technique, with poor reproduc-ibility. This attitude, however, ignores the fact that theseemingly chaotic variety of technical and interpreta-tional approaches is in fact a direct consequence of thetechniques major advantage: Breast MRI, compared tomammography, for example, yields a wealth of informa-tion on the tissue under investigation, including cross-sectional morphology as well as tissue relaxation times,perfusion, and diffusion as revealed by contrast en-hancement kinetics. Yet, understandably, and as a di-rect consequence, it will take longer to reach consensuson what is diagnostically relevant if one has aboutseven different criteria to work outas opposed to, e.g.,the situation in mammography, in which merely two

criteria (morphology and x-ray density) contribute tothe diagnosis. Today, the breast MRI community is nav-igating toward a consensus in terms of indications,techniques, diagnostic criteria, and overall appraisal ofthe techniques clinical use. There is broad agreementthat information on contrast enhancement kinetics asprovided by dynamic breast MRI should not be used asstand-alone diagnostic criteria, but must be inte-grated into the process of lesion differential diagnosis toimprove the early detection and correct classification of

breast cancer.

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